Epilepsy affects 1% of the population. Two thirds of individuals with epilepsy will respond to antiepileptic medications and the remaining third are medically intractable, i.e. do not respond to antiepileptic medications. In the United States, 3 million people have epilepsy making the intractable population close to 1 million individuals. Existing technology has resulted in very limited benefits in terms of controlling seizures in patients with intractable partial or generalized epilepsy.
Although the neural mechanisms that underlie consciousness are unclear, clinicians tend to separate it into wakefulness and awareness. Wakefulness depends upon the functional integrity of subcortical arousal systems in the brainstem and thalamus [1]. Awareness refers to the content of experience as regards both the environment and the self, and is thus defined as the capacity to respond to external stimuli while having an internal and qualitative experience of existence. The external awareness network seems to encompass bilateral dorsolateral prefrontal cortices and lateral posterior parietal cortices, whereas the internal awareness network seems to include midline posterior cingulate cortex/precuneus and anterior cingulate/medial prefrontal cortices [2]. A complete disruption of consciousness during the waking state, involving the perception of both external and internal stimuli, is experienced in many medical conditions that affect the brain primarily or secondarily including, though not limited to, coma and epilepsy, regardless of the area of seizure origin in the brain. Indeed, disruption of consciousness is one of the most disabling manifestations of epileptic seizures that affects the quality of life [3]. However, the precise structures and pathophysiological mechanisms involved in impairment of consciousness in epileptic seizures remain a matter of debate [4-6].
Common brain regions are thought to be involved in all seizures that interfere with consciousness, regardless of their onset zones and variations in semiology. These regions include the fronto-parietal association cortex and the subcortical arousal system in the brainstem and thalamus [6]. One hypothesis suggests that alteration of consciousness in partial seizures results from abnormal synchronization of cortical activity between distant brain regions [4] that overloads the structures involved in consciousness processing, affecting their ability to handle incoming information [5, 7].
As discussed in WO2014/113578, which is hereby incorporated by reference, temporal lobe epilepsy is the most common focal epilepsy in adolescents and adults, and the most frequent indication for epilepsy surgery. Mesial temporal lobe epilepsy (MTLE) often originates from the hippocampus, which is implicated in declarative memory function. A clinical trial in patients with intractable MTLE showed that temporal lobectomy is superior to continued medical therapy in achieving seizure freedom. However, resection is generally eschewed if pre-surgical evaluation predicts functional deficits. Additionally, more than half of all intractable patients are not candidates for surgical resection. The risk of memory decline after hippocampal resection depends on the structural integrity of the hippocampus and its degree of contribution to memory function prior to surgery. A non-lesional, language dominant hippocampus and good preoperative memory function often exclude MTLE patients from temporal lobectomy because of the high-risk of postoperative memory decline. This underlies the need to pursue controlling disabling hippocampal seizures without compromising memory function.
While surgical resection of the temporal lobe is an effective treatment for medically-intractable temporal lobe epilepsy, surgical resection often results in memory impairment. Thus, other approaches including deep brain stimulation (DBS) have been undertaken. Additionally, seizures may original from some brain regions that subserve important functions (e.g., movement or speech, etc.) and thus the patient is not a candidate for surgical resection. DBS in epilepsy has targeted gray matter structures using high frequencies, but has not achieved desired results. Conventional DBS may provide a first stimulation when there is no prediction of an impending seizure but may provide a second altered stimulation based on a prediction of an impending seizure, where the prediction is based on monitoring naturally occurring, organically generated signals. For example, conventional systems may be programmed to detect and record seizure activity based on signals generated naturally in the brain by the brain itself. Conventional systems may also be configured to control stimulation as a function of the detected or recorded seizure activity.
DBS has risen as an effective treatment in patients with movement or psychiatric disorders. The stimulation targets specific areas in the brain, altering the function of circuits or inducing neurogenesis and other plastic changes. DBS has been approved for treatment of Parkinson's disease, essential tremor, dystonia, and obsessive-compulsive disorder, but its success in epilepsy has been limited. Most stimulation trials in epilepsy have used high frequencies.
The claustrum is a telencephalic subcortical structure. It is a thin sheet of grey matter underneath the insula, which is part of the neocortex. The claustrum is a curved sheet that is oriented sagittally between the white matter tracts of the external capsule and extreme capsule. It is lateral to the putamen and medial to the insular cortex and is considered by some sources to be part of the basal ganglia. There are lateral and medial tracts connecting the claustrum to many parts of the cortex and perhaps to the hippocampus, the amygdala, and the caudate nucleus (connections with subcortical centers are a matter of debate). One claustrum is present on each side of the brain. Although the exact function of the claustrum remains to be verified, connectivity studies have shown that the claustrum plays a strong role in communication between the two hemispheres of the brain, specifically between cortical regions controlling attention. See Wikipedia, Claustrum.
The piriform cortex situated caudally to a dorsal area, which is caudal to a hippocampal area. The piriform cortex contains a critical, functionally defined epileptogenic trigger zone, “Area Tempestas”. From this site in the piriform cortex chemical and electrically evoked seizures can be triggered. It is the site of action for the proconvulsant action of chemoconvulsants. See Wikipedia, Piriform Cortex.